Sympathomimetic preparation



March 13, 1956 R. H. BLYTHE 2,733,303

SYMPATHOMIMETIC PREPARATION Filgd July 18, 1952 Fig.

IN VEN TOR. RUDOLPH H. BLYTHE ATTOR NEYS United States Patent SYMPATHOMIMETIC PREPARATION Rudolph H. Blythe, Llanerch, Pa., assignor to Smith, Kline & French Laboratories, Philadelphia, Pa., a cor poration of Pennsylvania Application July 18, 1952, Serial No. 299,566

5 Claims. 1 (Cl. 167-82) V .In accordance with this invention one of the above.

sympathomimetic agents, or a combination thereof, is continuously released over a long period of time through the use of a large number of small pellets coated with vari-f ous thicknesses of a material slowly digestible or dispersible in the gastrointestinal tract.

- It has been unexpectedly found that the preparation in accordance with this invention controls the level of sleep. throughout the entire period of sleep. By this invention it is practical to accurately control body levels so as to provide a desired level of sleep. The benefits stemming from this result are numerous. Of particular-im -i portance, it has been found that the preparation of this invention controls nocturnal seizures associated with epilepsy. Other involuntary reactions occurring during sleep, such as eneuresis, are similarly controlled. -Again,

unexpectedly, the preparation of this invention controls the incidence ofmigraine headaches occurring on awakening.

.Further, when used as anobesity remedy, the .con-,

stant release of the medicament of this inveu'tionover a ten to twelve hour period controls the appetiteuniformly throughout the waking hours and hence eliminates oneof the greatest factors contributing to obesity, namely, snack ing at times other than at regular meal times. i

Other beneficial and surprising results have also'be'en noted. Single doses produce jitteriness at peak body levels and subsequently produce mood let-down and i ritability on dropping to a low body level. These undesirable jside effects have been substantially eliminated.

Ari unexpected increase in the feeling of well being isalso achieved. h g V Again, this invention has surprisingly resulted in a verygreat increase in'reliability, since it has overcome theproblem occurring with the single large dosage fo'rm heretofore used which frequently became struck en route to the intestines with the resulting delay in medication.' Further, theme of a large number of small-pellets results in their wide dispersal throughout the intestines.

The dosage unit form in accordancewith this i'n'ven-.

tion comprises a capsule containing an initialdose of 2 tol0 mg. of the selected sympathomimetic; WhlCh'iS ready for immediate release to the body, being. freev of] any time-delay coating. This 2 to 10 mg. of the selected.

sympathomimetic can ,be in the form of numerousuncoated pellets made as described hereafter, or ca r es simply the crystalline orpowde'red form of' the selected sympathomimetic. This dosage is an amount suflicient to: substantially immediately raise the body level" tothef "ice 2 optimum eifective range. The normal single dosage is larger than the initial dose of this invention in order to achieve long action and results in numerous side efiects at peak body levels, particularly jitteriness, subsequent let-down and depression of mood.

In the case of a dextro-amphetamine salt this initial dosage preferably should be from 3 to 5 mg. In the case of a racemic amphetamine salt this initial'dosage preferablyshould be from 5 to 10 mg. In the case of a dextro-desoxyephedrine salt this initial dosage preferably should be from 2 to 5 mg. In the case of a racemic desoxyephedrine salt this initial dosage preferably should be from 4 to '10 mg. I

In addition the capsule contains-from 50 to about 400*, preferably about 100, wax-fat covered-pellets of these lected sympathomimetic, each coated pellet containing about the'same amount. of drug. The wax-fat coatings are selected so as to provide a continuous release ofthe selected sympathomimetic in an amount to maintain substantially constant the body level established by t he un-. coated amount of the selected sympathomimetic. These coated pellets will contain a total amount of the-selected sympathomimetic of from about 200% to 400% by:

weight of the uncoated initially released dosage.

Where desired, a sedative,

(amoharbital), 5-phenyl-5-ethylbarbituricacid (phenobarbital), 5 ethyl 5-(1-methylbutyl)-barbituric acid The addition of the sedative permits the use of the invention inpatients who are very sensitive to sympa thornimetics and provides a quieting efiect without the depression usually associated with sedatives.

The desired product can be achieved, for example, by combining the uncoated selected sympathomimetic with a plurality of different groups of coated pellets. It. Is preferred to use 3 groups as a practical matter, but I from two to eight groups are satisfactory. It has been found that if the required thickness of coating for release at the end of nine hours is X and the number of coated groups is Y, the first coated group may haveI-a median coating of X/Y, the next group a median coating of 2X/Y, the next 3X/Y, and so on, depending on the number of groups. Following-this formula, it has been found that if either of the following techniques are used to make a predetermined mediancoatin g-for'any one group, the coatings will vary 'within the rangeof from about 30% to about 40% on either side of the median coating. A satisfactory approximation is achieved where the median coating weights are made up using the above formulae with X representing the weight of the median coating of the .group which is released last.

Sympathomimetic pellets in accordance with this invention are readily prepared by utilizing a crystalline or powder form of the selected sympathomimetic and sucrose using procedure well-knownto the art for making sugar pellets (see, for example, Confectioners Journal, January 1951, page 41) By way of more specific example, following the teachings ofthis publica-' tion 20.0 kg. of extended d amphetamine sulfate is prepared from a mixture of 2.2 kg. of crystalline d-amphet amine sulfate and 17.8 kg. of sucrose. About 200 pellets having a mesh size of from 12-40 are screened outper such as, for example, a" barbiturate, such as S-isoamyl-S-ethylbarbituric acid Parts by weight Sucrose 100 Gelatin 8: Acacia 6 Water 70 If desired, the powdered sympathomimetic can be extended with; for example, calcium sulfate dihydrate, powdered starch or powdered acaeia'prior to being used'in'th'e process. The coating operation is repeated until each pellet contains thedesired amount of selected sympathemimetic. After the sympathomimetic pellets have been formed, a number of them are provided with a waxfat' coatingwhich' iscapable of being slowly disintegrated inthe gastro-intestinal tract. Such coatings and their application are all well known to the art, the most common method being. to place: the desired wax-fat combination in solution and spray it over the pellets during the operation ofjthe coating'pan holding the pellets.

The wax-fat coating will preferably be a mixture of glyceryl monostearate and beeswax, the glyceryl monostearate being within the range of from 50 to 95% by weightof the total coating. It is preferred to have the glyceryl monostearate about 90% by Weight of the total coating. Any other water-insoluble ingestible wax can be substituted for beeswax. Thus, for example, Japan wax, parafiin, carnauba wax, bayberry wax, and other animal, insect, plant or other water-insoluble, non-toxic, wax-like substances, such as sterols, as, for example, cholesterol, are satisfactory. Any other slowly digestible or'dispersible solids, such as slowly digestible fatty esters,. slowly dispersible fatty acids and slowly dispersible higher fatty alcohols may be used in place of glyceryl monostearate; Thus, for example, stearic acid, palmitic acid, glyceryl tristearate, cetyl palmitate, diglycol stearate, glyceryl myristate, triethylene glycol monostearate,. cetyl alcohol, stearyl' alcohol, and the like, are satisfactory. It

is'preferrcd to. use solid fatty acids and alcohols having.

from 12' to 22carbon atoms or esters of said solid fatty acids.

In order to: spray the wax-fat coating, the wax-fat constituent canhe admixed with a suitable warmed solvent such as carbon tetrachloride heated to about 60 C.,,thej

wax-fatisolids'being' within the range of from 25%' by weight of the; solution.

Mixturesof the. selected sympathomimetic and sedative can be' similarly prepared as pellets and coated.

It will be appreciated that the above described method is-merely illustrative of how the product of this invention can be achieved, there being multitudinous other equally= satisfactorymethods within the scope of the invention.

- This invention will be further clarified by reading'the following description in'conjunction with the drawings, in Which:.

Figure l. is a plan view of a capsule containing pellets inaccordance with this invention.

Figure 2 is a sectional view of typical pellets contained in the capsule of Figure 1.

As shown. inFigure l a two piece gelatin capsule2 contains. pellets 3 of a selected. sympathomimetic, the pellets being uncoated. Capsule 2 further contains waxfat. coated sympathomimetic pellets 4, 6-and8. Aswill; be apparent from a study of Figure 1, these various pellets are in random distribution, there being approximately an equal number of each group or type of pellet.

As shown in Figure 2, each of the pellets 4, 6 and 8 has a center or core 10 of the selected sympathomimetic. The pellets 4 have a wax-fat coating 12 which is of greater thickness than the wax-fat coating 14 of pellets 6, which in turn is of greater thickness than the wax-fat coating 16 of pellets 8. Coatings 12, 14 and 16 shownin Figure 2 represent the median coatings of the groups formed. by pellets 4, 6 and 8, it being appreciated that as previously described the coatings of each group of pellets will. vary in order to provide gradual release of the selected sympathomimetic over a ten to twelve hour period.

The following examples are illustrative of dosage unit forms in accordance with this invention and their preparation:

Example 1 15.5- kg. of non-pareil seeds (sugar pellets) all passingthrough a- 12 mesh screen, passing through a 40 mesh screen and not over 10% through a 28' mesh screen, were placed in a 36'' inch coating pan. The pan Was'set in rotation and 240 cc. of syrup U. S. P. was added by slowly pouring it on the pellets to evenly wet them. 7 50' grams'of powder, consisting of 80% dextro-amphetamine sulfate and 20% calcium sulfate dihydrate was sprinkled on the wetted mass of non-pareil seeds. The'pellets' were dried in warm air. The addition of the syrup, dextroamphetamine' sulfate, coatingpowderand the dryingwere repeated to' apply three additional coats. Talc as a fifth c'o'at: was added by wetting the pellets with 240 cc. of syrup and then dusting on 600 gm. of tale. The pellets were rolled until dry and the excess talc wa's'removed by vacuum. 20.0 kg. of dextro-amphetamine sulfate coated pellets were yielded through a 12 mesh screen; Onequarter of theyielded pellets were removed and' set aside.

The three-quarters of the batch remaining in the coating pan wascoated with a wax-fat coating solution made by admixing 6300 gm. glyceryl monostearate, 700 gm. white beeswax (U. S. P.) and 21,000 cc. of carbon tetrachloride. The wax fat solution was at a temperature of 70 C.

Afterapplying 425 cc; of wax-fat solution, the' pellets were-dried with air and the coating operation repeated until the weight 'of thematerial being coated had increased 10%, at. which point one-third of the remainingbatch' was removed and dusted with tale in a separate coating pan;

The remainder of the. batch was further repeatedly eoate'd'with the wax-fat solution and dried until the weight of the material increased 10%, over what it. weighed when it was separated from the'first' group of coated pellets, at'which time one-half of the remaining pellets were removed and dusted with tale in a separate coating. pan.

The remaining'pellets' were subjected tofurther'repeate'd' coating with the wax-fat solution and dryinguntil' the weight of' this group of'pellets had 'increased about 10% over the weight of the group from. which.it had been separated immediately previously. These pelletswere thendustedwith talc.

weight of coating, of. the group involved.

The :four' groups of'pellets-thus formed were all placed in a single container and thoroughly mixedvto provide a-.unifonn. mixture;

Size No; 3' gelatin capsules were then filledwith the thusmixed pellets to provide a total dosageof' 15 mgs; ofdextro-amphetamine sulfate per capsule. Each capsulecontained about pellets.

Each No; 3 capsule providedthe desired 'body'level of" dextroaampheta'minesulfate in about one-half hour. The coated. groups provided a continuous release of dCXtl'Ov amphetamine sulfate and. maintained this desired body. level for approximately eleven hours.

The weight of the coating of each group was foundto vary about :L-35% of the median Example 2 The steps of Example 1 were repeated with the exception that d-desoxyephedrine hydrochloride was substituted for dextro-amphetamine sulfate.

Example 3 The steps of Example 1 were repeated with the exception that racemic amphetamine phosphate was substituted for dextroamphetamine sulfate and No. 1 gelatin capsules used. v

Example 4 The steps of Example 1 were repeated with the exception that racemic desoxyephedrine citrate was substituted for dextroamphetamine sulfate and No. 2 gelatin capsules used.

Example 5 d-Amphetamine sulfate 500.0

(Passed through #80 mesh screen) The pellets were then dried using warm air. The addition of the warm gelatin coating solution, amobarbitaldextro-amphetamine sulfate coating powder was repeated 18 times. The pellets were dried with warm airand loose powder in pan was sucked out with a vacuum. The product was freed of lumps by passing through a #14 screen and /3 of the yield was set aside.

The twothirds of the batch remaining in the coating pan was coated with a wax-fat coating solution, made by admixing 1800 grams of glyceryl monostearate, 200 grams of white beeswax (U. S. P.), and 6,000 cc. of carbon tetrachloride. The wax-fat solution was at a temperature of 70 C. After applying 300 cc. of wax-fat solution, the pellets were dried with air and the coating operations repeated until the weight of the material being coated had increased 12.5%. At this point, one-half of the waxfat coated pellets were removed from the pan and set aside to dry overnight.

The remaining pellets in the coating pan were subjected to further repeated coating, using the warm waxfat solution until the batch of the material being coated had increased an additional 12.5% in weight. The coated pellets were then dried overnight.

The three groups of pellets thus formed were all placed in a single container and thoroughly mixed to provide a uniform mixture.

No. 1 gelatin capsules were then filled with the thus mixed pellets to provide a total dosage of 97.5 mg. of amobarbital and 15 mg. of dextro-amphetamine sulfate. Each capsule contained about 350 pellets.

Each #1 capsule provided the desired body level of amobarbital and dextro-amphetamine sulfate in about 45 minutes. The coated groups provided a continuous release of amobarbital and dextro-amphetamine sulfate and maintained this desired body level for approximately 12 hours.

It is not desired to be limited except as set forth in the following claims, the above description being by way of illustration only.

What is claimed is:

l. A therapeutic preparation in dosage unit form comprising a capsule containing an initial dosage of from 2 to mg. of sympathomimetic selected from the group consisting of a salt of racemic amphetamine, a salt of dextro-amphetamine, a salt of racemic desoxyephedrine anda salt of dextro-desoxyephedrineto provide a pre? I of said initial dosage and having ingestible coatings resistant to disintegration in the gastro-intestinal tract, the coatings being of varying thicknesses to provide for the gradual release of, the selected sympathomimetic, said preparation maintaining a substantially constant body level of the selected sympathomimetic over a period of about ten to twelve hours.

2. Atherapeutic preparation in dosage unit form com.- prising a capsule containing an initial dosage of from 2 to 10 mg. of a sympathomimetic selected from the group consisting of a salt of racemic amphetamine, a salt of dextro-amphetamine, a salt of racemic desoxyephedrine and a salt of dextro-desoxyephedrine to provide a predetermined body level of the selected sympathomimetic, 50 to about 400 pellets containing the selected sympathomimetic in an amount of about 200 to 400% by weight of said initial dosage and having ingestible waxfat coatings resistant to disintegration in the gastro-intestinal tract, the coatings being of varying thicknesses to provide for the gradual release of the selected sympathomimetic, said preparation maintaining a substantially constant body level of the selected sympathomimetic over a period of about ten to twelve hours.

3. A therapeutic preparation in dosage unit form comprising a capsule containing an initial dosage of from 2 to 10 mg. of a sympathomimetic selected from the group consisting of a. salt of racemic amphetamine, a salt of dextro-amphetamine, a salt of racemic desoxyephedrine, and a salt of dextro-desoxyephedrine and a sedative to provide a predetermined body level of the selected sympathomimetic, 50 to about 400 pellets containing the selected sympathomimetic in an amount of about 200 to 400% by Weight of said initial dosage and a sedative and having ingestible Wax-fat coatings resistant to disintegration in the gastro-intestinal tract, the coatings being of varying thicknesses to provide for the gradual release of the selected sympathomimetic, said preparation maintaining a substantially constant body level of the selected sympathomimetic over a period of about ten to twelve hours.

4. A therapeutic preparation in dosage unit form com prising a capsule containing an initial dosage of from 2 to 10 mg. of sympathomimetic selected from the group consisting of a salt of racemic amphetamine, a salt of dextro-amphetamine, a salt of racemic desoxyephedrine and a salt of dextro-desoxyephedrine to provide a predetermined body level of the selected sympathomimetic, a minimum of 50 pellets containing the selected sympathomimetic in an amount of about 200 to 400% by Weight of said initial dosage and having ingestible coatings resistant to disintegration in the gastro-intestinal tract, the coatings being of varying thicknesses to provide for the gradual release of the selected sympathomimetic, each of said pellets having a substantially spherical core containing the selected sympathomimetic, and said preparation maintaining a substantially constant body level of the selected sympathomimetic over a period of about ten to twelve hours.

5. A therapeutic preparation in dosage unit form comprising a capsule containing an initial dosage of from 2 to 10 mg. of sympathomimetic selected from the group consisting of a salt of racemic amphetamine, a salt of dextro-amphetamine, a salt of racemic desoxyephedrine and a salt of dextro-desoxyephedrine to provide a predetermined body level of the selected sympathomimetic, a minimum of 50 pellets containing the selected sympathomimetic in an amount of about 200 to 400% by weight of said initial dosage and having ingestible coatings resistant to disintegration in the gastro-intestinal tract, the coatings being of varying thicknesses to provide for the gradual release of the selected sympathomimetic, each of said avasasw 7. pellets havinga. substantially spherical c'ore' containing 2,540,979 the selected sympatli'omiinetib with the. medicament oVer- 2',6 1 9 i4'47 lying a substantially spherical innocuous seed; and said preparation maintaining a substantially constant'- body level of the selected sympatliomimetic over a period of 5 102438 about ten to twelve hours.

References Cited in the" file of this patent UNITED STATES PATENTS Miller July 16,- 1940 Goggin Jan. 2, 1951 Clymer etai; Feb. 6, 19 51 Malawi ev ali NovL-ZS; 195 2 Drug Trade': NeWs=voli1me= 27,-No; 64; February' 18,

1952;pa'ge 5 2;

Clinical Medicine, September 1948, page 16.

Chain Store Age, Drug Store Mgr.s ed., sec. 1, June 

1. A THERAPEUTIC PREPARATION IN DOSAGE UNIT FORM COMPRISING A CAPSULE CONTAINING AN INITIAL DOSAGE OF FROM 2 TO 10 MG. OF SYMPATHOMIMETIC SELECTED FROM THE GROUP CONSISTING OF A SALT OF RACEMIC AMPHETAMINE, A SALT OF DEXTRO-AMPHETAMINE, A SALT OF RACEMIC DESOXYEPHEDRINE AND A SALT OF DEXTRO-DESOXYEPHEDRINE TO PROVIDE A PREDETERMINED BODY LEVEL OF THE SELECTED SYMPATHOMIMETIC, A MINIMUM OF 50 PELLETS CONTAINING THE SELECTED SYMPATHOMIMETIC IN AN AMOUNT OF ABOUT 200 TO 400% BY WEIGHT OF SAID INITIAL DOSAGE AND HAVING INGESTIBLE COATINGS RESISTINGS BEING OF VARYING THICKNESS TO PROVIDE FOR THE GRADUAL RELEASE OF THE SELECTED SYMPATHOMIMETIC, SAID PREPARATION MAINTAINING A SUBSTANTIALLY CONSTANT BODY LEVEL OF THE SELECTED SYMPATHOMIMETIC OVER A PERIOD OF ABOUT TEN TO TWELVE HOURS. 